The development of obesity is multifactorial and includes interactions between variant alleles and environments that predispose individuals toward development of the disease. Other components of obesity, based on variations in epigenetic programming, have been established by the strong evidence obtained from human epidemiological and animal studies that link nutritional status during in utero and early post-natal growth to the development of obesity and diabetes in adults. However, the mechanisms associated with these epigenetic contributions to obesity are difficult to study because of the lack of a good experimental model or appropriate gene targets. To investigate epigenetic contributions to obesity, we have developed an animal model based upon phenotypic variation of obesity in genetically identical mice. Using global gene expression analyses, we have identified a set of coordinately regulated developmental genes in adipose tissue that are associated with the development of a robust obesity phenotype in mice after feeding a high fat diet. These genes include an antagonist of Wnt signaling, secreted frizzled related protein 5 (Sfrp5) and the imprinted gene mesoderm specific transcript (Mest). Additionally, variations of Sfrp5 and Mest expression in adipose tissue biopsies performed on young mice prior to exposure to dietary fat can predict animals that were most susceptible to the development of dietary fat- induced obesity at a later age. In this proposal, we will use a retroviral-delivered inducible transgenic approach to examine the mechanism associated with the coordinated regulation of Sfrp5 and Mest and to determine how these genes modulate lipogenesis and adipocyte differentiation. We will also identify genomic targets associated with variable expression of Sfrp5 and Mest in adipose tissue to determine whether epigenetic differences are present within these elements. The results of these experiments will begin to elucidate unique biological mechanisms linked to epigenetic programming that are associated with variations of adiposity in the absence of genetic variation. Future experiments will evaluate these mechanisms and associated genes as potential therapeutic targets for the treatment of obesity. PUBLIC HEALTH RELEVANCE Many studies have shown that nutritional status during development can permanently alter an individual's susceptibility to developing diseases such as obesity and diabetes, however, very little is known about the biological mechanisms that cause these changes. Therefore, we characterized a mouse model that has no genetic differences between individuals to study the basis for these permanent alterations, and have identified several genes that are associated with variations in obesity. We propose to study how two of these genes, mesoderm specific transcript and secreted frizzled related protein 5, function in order to determine whether they could be good therapeutic targets for the treatment of obesity.